Glassy-crystalline material with low solubility and process of preparing the same

ABSTRACT

The invention refers to a material which is chemically long-term stable in a neutral or slightly acid environment and which can be used both as bioactive bone replacement material, e.g. in the form of a coating applied onto metallic prosthesis sticks by thermal spraying, and as substrate material in biotechnology, e.g. in the form of a ceramic sheet. According to the invention, said material comprises 15-45% by weight CaO, 40-45% by weight P 2 O 5 , 10-40% by weight ZrO 2  and fluoride, said material further comprises two crystalline phases being apatite and calcium zirconium phosphate, and a secondary glass phase. Said material has a very high chemical long-term stability, compared to known materials which can also be produced by means of a melting process.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] The invention refers to a glassy-crystalline material with lowsolubility which can be used both as bioactive bone replacementmaterial, e.g. in the form of a coating applied onto metallic prosthesissticks by thermal spraying, and as substrate material in biotechnology,e.g. in the form of a ceramic sheet or body. The invention also refersto a manufacturing method.

[0003] 2. Description of the Related Art

[0004] In principal, long-term stable inorganic materials are known.Materials that are specifically used as bioactive bone replacementmaterials and have a sufficient long-term stability have also beendescribed in the relevant literature. For example, there have beencontinuous publications dedicated to the successful clinical use ofglass ceramics and sintered glass ceramics the main crystal phases ofwhich are apatite and wollastonite [Kokubo, T., Biomaterials, 12 (1991)155-163; Berger, G. et al.: Long-term stable bioactive glass ceramics asimplant material—ten years of clinical experience, Fourth WorldBiomaterial Congress, Berlin, Apr. 24-28, 1992, Transactions p. 33]. Thechemical stability of the aforesaid materials has been surpassed by thatof other bioactive materials on the basis of calcium-zirconium/titaniumphosphate (Biomaterials 18 (1997) 1671-1675) which can only bemanufactured using ceramic methods, but do not melt at temperatureswhich are common in the glass industry (approximately 1650° C.), whichis known to cause disadvantages as regards the mechanical stability ofsuch granulated materials and particularly of bodies manufactured

[0005] The object of the invention is to provide a glassy-crystallinematerial, which enables bones to be directly joined with no connectivetissue in between and which at the same time is long-term stable.

SUMMARY OF THE INVENTION

[0006] According to the invention, the glassy-crystalline material onthe basis of CaO, P₂O₅, ZrO₂ and fluoride consists of 15-45% by weightCaO, 40-45% by weight P₂O₅, 10-40% by weight ZrO₂ and 0.7-3.5% by weightof fluoride and contains apatite and calcium zirconium phosphate as maincrystal phases and a glass phase as secondary component, the maincrystal phases jointly making up at least 35% by weight and thesecondary components making up 5 to 15% by weight, and all percentagesbeing relative to the total weight of the glassy-crystalline material.

BRIEF DESCRIPTION OF THE DRAWINGS

[0007] In the following the invention will be described in greaterdetail on the basis of an embodiment schematically represented in thefigures. There is shown

[0008]FIG. 1 shows an X-ray diffraction diagram of the materialaccording to Example 1,

[0009]FIG. 2 shows an X-ray diffraction diagram of the materialaccording to Example 2.

DETAILED DESCRIPTION OF THE INVENTION

[0010] A preferred glassy-crystalline material contains 23-39% by weightCaO, 40-45% by weight P₂O₅, 20-35% by weight ZrO₂ and 1-3% by weight offluoride and contains apatite and calcium zirconium phosphate as maincrystal phases and a glass phase as secondary component, the maincrystal phases jointly making up at least 35% by weight and thesecondary components making up 5 to 15% by weight.

[0011] Another preferred glassy-crystalline material contains 20-35% byweight CaO, 40-45% by weight P₂O₅, 20-35% by weight ZrO₂ and 1-3% byweight of fluoride and in addition 0.1 to 6% by weight Na₂O and containsapatite and calcium zirconium phosphate as main crystal phases and aglass phase as secondary component and in addition a sodium zirconiumphosphate phase as secondary component. In this material, the maincrystal phases jointly make up at least 35% by weight and the secondarycomponents can make up 5 to 15% by weight each.

[0012] Further, the glassy-crystalline material according to theinvention can additionally contain 0.1 to 6% by weight of magnesiumoxide and/or potassium oxide and, if so, the corresponding phases assecondary components.

[0013] The Na₂O, MgO and/or K₂O content is preferably in the range of 1to 6% by weight. The content of the corresponding sodium zirconiumphosphate secondary crystal phase is preferably in the range of 5 to 10%by weight.

[0014] In an advantageous embodiment, up to 15% by weight of a groundglass can be added to the mixture to be melted, which ground glassconsists of SiO₂, Al₂O₃ and MgO and in some cases CaO and thecomposition and characteristics of which correspond to those of acordierite glass, which considerably improves the sintering activity ofthe glassy-crystalline material according to the invention. Such anadded glass has a particularly high melting point (>1500° C.) and ischemically stable as regards the influence of water, acids and alkalinesolutions.

[0015] The terms “glass ceramics” and “glassy-crystalline material” usedherein cannot always be clearly defined. Both crystalline and glassy orX-ray amorphous phases are present in a thoroughly mixed state. It is ofno importance for the present invention whether one phase is locatedadjacent to the other or one phase encloses the other. The term “maincrystal phase” refers to a crystalline phase, which is contained in atleast twice the amount of a secondary phase, concentrations ofapproximately 15% by weight and below, preferably below 10% by weight,being referred to as secondary phases.

[0016] Surprisingly, the solubility of the material has been found to bevery low, even in a slightly acid medium as observed in the case ofinflammatory reactions, i.e. pH=6.0, although the said material containsapatite [Berger et al., Hydroxyapatite's solubility may cause looseningof coated implants, Bioceramics Vol. 13, edited by Santro Giannini andAntonio Moroni (Proceedings of the 13th International Symposium onCeramics in Medicine); Trans Tech Publ. Ltd, Swiss, 2000, 111-114].

[0017] Further, it has surprisingly been found that, after an initialalkaline reaction, the surface properties of the material (theglassy-crystalline material) change towards physiological pH values(7.4) if the said material is stored in deionized water, due to which itis of interest to biotechnology.

[0018] In addition, the material according to the invention could not beexpected to surprisingly be processable into slurries, which aresuitable for manufacturing spongiosa-like bodies and ceramic sheetssince there are numerous examples of known materials in the relevantliterature, which do not have these characteristics.

[0019] The thermal coefficient of expansion of the new material is inthe range of 1.4 and 6×10⁻⁶ degrees⁻¹ between 27° C. and 300, 400, 600or 800° C. It is in the range of 1.4 and 8×10⁻⁶ degrees⁻¹ between 27° C.and 300, 400, 600 and 800° C. if the manufacturing process of thematerial includes holding stages during the cooling down of the meltedmass, as described below.

[0020] Another characteristic feature of the material consists in thatit has a total solubility of 4 to 5.5 mg/l if the test is carried out ina 0.2 M TRIS HCl buffer solution at pH=7.4, T=37° C., using a grain sizefraction of 315-400 im, the duration of the test being 120 h and theratio of surface area (sample) to volume (solvent) being 5 cm⁻¹.

[0021] Another characteristic feature of the material consists in thateven storage in water (144 h) at 37° C. causes the surface of thematerial to change so that physiological pH values of approximately 7.4can be measured. If the temperature of the water bath is increased, thechange of the surface properties is accelerated accordingly.

[0022] Glass ceramics having the following characteristics can beobtained if the manufacturing process of the material according to theinvention includes one or two holding stages during the cooling down ofthe melted mass in the furnace between 800 and 1100° C., as in a furtherembodiment described below:

[0023] a total solubility of 0.2 to 2.0 mg/l if the test is carried outin a 0.2 M TRIS HCl buffer solution at pH=7.4, T=37° C., using a grainsize fraction of 315-400 μm, the duration of the test being 120 h andthe ratio of surface area (sample) to volume (solvent) being 5 cm⁻¹,

[0024] a thermal coefficient of expansion between 1.4 and 8×10⁻⁶degrees⁻¹ between 27° C. and 300, 400, 600 and 800° C.,

[0025] stability in the pH range between 7.0 and 7.5.

[0026] The chemical stability of such a material is therefore 3 to 10times higher than that of a material manufactured without holding stagessince the total solubility is in the range of 0.2 to 2.0 mg/l.

[0027] According to the invention, the material is manufactured bycombining the substances which are suitable for forming the mixture,i.e. 15-45% by weight CaO, 40-45% by weight P₂O₅, 10-40% by weight ZrO₂and 0.7-3.5% by weight of fluoride, and melting them at 1550 to 1650° C.using suitable, usually multistage thermal treatment programs (holdingstages in the range of 400 to 1500° C.) and a suitable cruciblematerial, e.g. consisting of a Pt/Rh alloy. The melted mass is pouredout and once the mass has solidified it is cooled down to roomtemperature in air (spontaneous cooling) or in a cooling furnace,depending upon its intended use, the cooling process including holdingstages if appropriate.

[0028] Holding stages in thermal treatment program of about each at 400,800 and 1000° C. can be added to improve the reproducibility of themelting reaction.

[0029] Advantageously, the fluoride is added in the form of CaF₂ and inconcentrations of 1.5-7% by weight. Alternatively, it can also be addedin the form of ZrF₂ or, as the case may be, NaF, KF or MgF₂.

[0030] In another embodiment, the method is characterized in that thesaid mixture of 15-45% by weight CaO, 40-45% by weight P₂O₅, 10-40% byweight ZrO₂ and 0.7-3.5% by weight of fluoride is melted at 1550 to1650° C., the melting process including several holding stages in therange of 400 to 1500° C., and is then cooled down in the furnace in acontrolled manner and at a rate of 60° C./h to 300° C./h, the coolingprocess lasting for 2 to 10 h and including two holding stages, oneholding stage between 1000 and 1100° C. and another one between 800 and1000° C.

[0031] Once the material has been cooled down it is e.g. ground, mixedwith commonly used sintering aids and pressed into bodies in order toobtain a densely fired ceramic body after sintering.

[0032] Alternatively, the material manufactured according to theinvention can e.g. be ground, mixed with commonly used sintering aidsand processed into a slurry which is then applied onto a polyurethanesponge and sintered in several sintering stages at such hightemperatures that the polyurethane sponge and the sintering aids areburnt completely and a spongiosa-like body is obtained the maincrystalline components of which are apatite and calcium zirconiumphosphate.

[0033] Another processing option consists in grinding the material,adding commonly used sintering aids and processing the slurry obtainedin this way into a sheet which has an open-pore structure once thefiring process has finished.

[0034] Another object of the invention consists in the use of theglassy-crystalline material according to the invention for themanufacture of granulated materials, ceramic bodies or ceramic sheetshaving a dense or open-pore structure.

[0035] The invention will hereinafter be explained in detail by way ofexamples. All percentages are by weight if not indicated otherwise.

EXAMPLES Example 1

[0036] A mixture is prepared the composition of which is as follows(code: Apatite/CZP1):

[0037] 25.88 CaO

[0038] 28.44 ZrO₂

[0039] 43.68 P₂O₅

[0040] 5.00 CaF₂

[0041] It is practicable to add the CaO portion in the form of 62.79CaHPO₄ and the P₂O₅ portion required in the form of 10.51 ml of a 85%H₃PO₄. First, CaHPO₄, ZrO₂ and CaF₂ are thoroughly mixed, subsequentlythe phosphoric acid is added and the reaction product is ground in amortar and put into a drying chamber, the drying process includingtemperature holding stages lasting for a total of 4 h in the range of120° C. to 170° C. The reaction mixture obtained is taken out and filledinto a Pt/Rh crucible and is heated, cooled down and ground in a mortar,the heating process including 1 h holding stages at 400 and 800° C. Thematerial pretreated in this way is now melted in a Pt/Rh crucible, themelting process including 15 min holding stages at 800, 1000, 1300, 1500and finally 1600° C., and subsequently poured onto a steel plate (roomtemperature).

[0042] Part of the solidified mass was pulverized by grinding it in anagate mill, particles below 43 μm were separated by sieving andsubsequently subjected to an X-ray diffraction analysis. The result (cf.FIG. 1) shows that the crystal phases apatite(fluorapatite/hydroxylapatite) and calcium zirconium phosphate[CaZr₄(PO₄)₆] are clearly detectable.

Example 2

[0043] A mixture according to the instructions of Example 1 is preparedexcept that sodium oxide is added as additional component (code:Apatite/CZP2). In this approach, the mixture is to be composed asfollows:

[0044] 59.93 CaHPO₄

[0045] 27.10 ZrO₂

[0046]3.42 Na₂O

[0047] 5.00 CaF₂ and

[0048] 9.56 ml of a 85% H₃PO₄ acid.

[0049] Processing was done as in Example 1. Following the lasttemperature holding stage, the melted mass was poured out of thecrucible onto a steel plate.

[0050] Part of the solidified mass was pulverized by grinding it in anagate mill, particles below 43 im were separated by sieving andsubsequently subjected to an X-ray diffraction analysis. The result (cf.FIG. 2) shows that the crystal phases apatite(fluorapatite/hydroxylapatite) and calcium zirconium phosphate[CaZr₄(PO₄)₆] and sodium zirconium phosphate [NaZr₂(PO₄)₃] aredetectable in the glassy-crystalline material.

Example 3

[0051] A glassy-crystalline material according to Example 1(Apatite/CZP1) is produced. The material is pulverized by grinding it ina mill lined with zirconium oxide so that a D₅₀ value of 8 mm isobtained. The ground material is mixed with a 5% polyvinyl alcohol (PVA)solution, the ratio of ground material to PVA solution being 90:10% byweight, and pressed into a stick at 4.7 kN in a stamping press. Thisgreen compact is sintered at a temperature of 1050° C.

[0052] Subsequently, the thermal coefficient of expansion (CE) of therelatively dense body obtained in this way is determined:

[0053] CE in the range of 27-400° C.: 1.90×10⁻⁶ degrees Celsius⁻¹

[0054] CE in the range of 50-400° C.: 1.86×10⁻⁶ degrees Celsius⁻¹

[0055] CE in the range of 30-300° C.: 1.45×10⁻⁶ degrees Celsius⁻¹

[0056] CE in the range of 30-400° C.: 1.88×10⁻⁶ degrees Celsius⁻¹

[0057] CE in the range of 30-600° C.: 2.6×10⁻⁶ degrees Celsius⁻¹

[0058] CE in the range of 30-800° C.: 3.2×10⁻⁶ degrees Celsius⁻¹

Example 4

[0059] A glassy-crystalline material according to Example 1(Apatite/CZP1) is produced. Subsequently, the material is ground in amortar and a grain size fraction of 315-400 μm produced.

[0060] The granulated material obtained in this way is compared with abasic glass (Ap40_(glass)) and an apatite and wollastonite-based glassceramic material produced from this basic glass (Ap40_(cryst.)) [i.e.chemical composition as follows (% by weight) 44.3 SiO₂; 11.3 P₂O₅; 31.9CaO; 4.6 Na₂O; 0.19 K₂O; 2.82 MgO and 4.99 CaF₂, manufactured accordingto patent DD 247 574] as regards chemical stability.

[0061] First, the specific surface areas were determined according toBET using krypton as measuring gas:

[0062] Apatite/CZP1: 0.364 m²/g

[0063] Ap40_(glass): 0.018 m²/g

[0064] Ap40_(cryst.): 0.055 m²/g.

[0065] It can be seen that the material according to the invention has acertain open porosity compared to the basic glass and the glass ceramicmaterial produced therefrom. In the solubility tests, these differencesare taken into account in that the ratio of surface area (samples) tovolume of solvent (TRIS HCl buffer solution) is adjusted to 5 cm⁻¹ inall cases.

[0066] A 0.2 M TRIS HCl buffer solution whose pH=7.4 at 37° C. was usedas solvent. The samples were stored therein at 37° C. for a period of120 h. Subsequently, the total solubility was determined by determiningthe individual ions (Ca, P, Zr) in the solution by means of an ICPmeasurement:

[0067] Apatite/CZP1: 4.1-5.1 mg/l

[0068] Ap40_(glass): 318-320 mg/l

[0069] Ap40_(cryst.): 75.2-82.0 mg/l.

[0070] These values impressively prove the high chemical stability ofthe material according to the invention under simulated physiologicalconditions, a known method for the in vitro determination of long-termstability.

Example 5

[0071] Processing is done as in Example 4, except that a 0.2 M TRIS HClbuffer solution whose pH value is 6.0 at 37° C. is used for measuring.In this way, it this possible to simulate a pH drop from thephysiological 7.4 value down into the acid range due to an infectionduring wound healing or at a later stage.

[0072] The following total solubility values (Ca, P, Zr) were determinedby means of ICP:

[0073] Apatite/CZP1: 16-19 mg/l

[0074] Ap40_(glass): 505-518 mg/l

[0075] Ap40_(cryst.): 117-125 mg/l.

[0076] These values impressively prove the high chemical stability ofthe material according to the invention under simulated conditions, asthey are present during an inflammatory reaction. According to thevalues measured, the increase of the absolute solubility values of thematerial according to the invention is much smaller than the ratherdramatic increase which has been determined for the basic glass and theapatite/wollastonite-based glass ceramic material.

Example 6

[0077] A glassy-crystalline material according to Example 2(Apatite/CZP2) is produced. The material is pulverized by grinding it ina mill lined with zirconium oxide so that a D₅₀ value of 8 μm isobtained. 100 g of this ground material is mixed with 45 g of a mixtureconsisting of 90% by weight of polyethylene glycol and 10% by weight ofa commercially available surface-active agent and with 5 ml isopropylalcohol so that a slurry is obtained. This slurry is applied ontoopen-pore PUR sponges whose porosity is between 80 and 20 ppi (pores perinch) by repeatedly immersing and squeezing the sponges, dried overnightin a drying chamber at 120° C. and subsequently heated slowly up to1050° C. at a rate of 1° C. per minute. The result is a spongiosa-likematerial the structure of which resembles that of the sponge used whilethe PUR sponge has burnt completely.

Example 7

[0078] A glassy-crystalline material according to Example 1(Apatite/CZP1) is produced. The material is pulverized by grinding it ina mill lined with zirconium oxide so that a D₅₀ value of 8 μm isobtained. 1 g of this freshly ground material is added to 100 ml of adeionized water according to ISO 3696 and the pH value change measuredover a period of 144 h.

[0079] Surprisingly it was found that the pH value of 8.8, which wasdetermined after the material, had been stored in deionized water forone hour decreases to the physiological value of 7.4 after 144 h, due towhich the said material becomes interesting to biotechnology, inparticular.

Example 8

[0080] A mixture according to the instructions of Example 1 is preparedexcept that the following component composition was selected (code:Apatite/CZP3):

[0081] 80.79 g CaHPO₄

[0082] 19.42 g ZrO₂

[0083] 4.87 g CaF₂ and

[0084] 0.62 ml of a 85% phosphoric acid.

[0085] Processing was done as in Example 1 except that the melted masswas not poured onto a steel plate, but cooled down in a defined mannerin the furnace, the cooling process including two holding stages at1050° C. (6 h) and 950° C. (6 h) . The total solubility of this materialis 0.81 mg/l if the test is carried out in a 0.2 M TRIS HCl buffersolution at pH=7.4, T=37° C., using a grain size fraction of 315-400 μm,the duration of the test being 120 h and the ratio of surface area(sample) to volume (solvent) being 5 cm⁻¹.

Example 9

[0086] A mixture according to the instructions of Example 8(Apatite/CZP3) is prepared, the component composition used being asfollows:

[0087] 37.38% by weight CaO

[0088] 14.45% by weight ZrO₂

[0089] 42.64% by weight P₂O₅

[0090] 5.53% by weight CaF₂

[0091] Further, 10% by weight of a ground glass (D₅₀=4.6 mm) composed asfollows:

[0092] 12.05% by weight MgO

[0093] 1.00% by weight CaO

[0094] 38.00% by weight Al₂O₃

[0095] 48.95% by weight SiO₂

[0096] was added to the aforesaid sintered and ground material in orderto improve its sintering activity.

[0097] Subsequently, the said materials mixture was processed accordingto Example 6 except that tempering was carried out as follows:

[0098] A PUR sponge onto which the slurry had been applied was heated upto 1300° C. at a rate of 700° C./h, the result obtained being aspongiosa-like body.

What is claimed is:
 1. A glassy-crystalline material with low solubilityon the basis of CaO, P₂O₅, ZrO₂ and fluoride which material comprises15-45% by weight CaO, 40-45% by weight P₂O₅, 10-40% by weight ZrO₂ and0.7-3.5% by weight of fluoride and contains apatite and calciumzirconium phosphate as main crystal phases and a glass phase assecondary component, the main crystal phases jointly making up at least35% by weight and the secondary components making up 5 to 15% by weight,and all percentages being relative to the total weight of theglassy-crystalline material.
 2. A material according to claim 1 whereinthe said material contains 23-39% by weight CaO, 40-45% by weight P₂O₅,20-35% by weight ZrO₂ and 1-3% by weight of fluoride.
 3. A materialaccording to claim 1 or 2 wherein the said material additionallycontains 0.1 to 6% by weight Na₂O, MgO and/or K₂O and correspondingphases as additional secondary component.
 4. A material according toclaim 1 wherein the said material additionally contains a sodiumzirconium phosphate phase.
 5. A material according to claim 1 whereinthe said material is present in the form of a granulated material or aceramically processed dense or porous body or a ceramic sheet.
 6. Amaterial according to claim 1 wherein the said material has one orseveral of the following parameters a total solubility of 0.2 to 5.5mg/l if the test is carried out in a 0.2 M TRIS HCl buffer solution atpH=7.4, T=37° C., using a grain size fraction of 315-400 mm, theduration of the test being 120 h and the ratio of surface area (sample)to volume (solvent) being 5 cm⁻¹, a thermal coefficient of expansionbetween 1.4 and 8·10⁻⁶ degrees⁻¹ between 27° C. and 300, 400, 600 and800° C., stability in the pH range between 7.0 and 7.5.
 7. A method formanufacturing a glassy-crystalline material according to claim 1 whereina mixture of 15-45% by weight CaO, 40-45% by weight P₂O₅, 10-40% byweight ZrO₂ and 0.7-3.5% by weight of fluoride is melted at 1550 to1650° C., the melting process including several holding stages in therange of 400 to 1500° C., and the glassy-crystalline material isobtained in the form of a melted mass which is cooled down spontaneouslyor step by step.
 8. A method according to claim 7 wherein an additional0.1 to 3% by weight Na₂O, MgO and/or K₂O are added to the said mixture.9. A method according to claim 7 wherein up to 15% by weight of a groundglass are added, which glass consists of SiO₂, Al₂O₃ and MgO and inoptionally CaO and the composition and characteristics of whichcorrespond to those of a cordierite glass.
 10. A method according toclaim 7 which method comprises melting of a mixture of 15-45% by weightCaO, 40-45% by weight P₂O₅, 10-40% by weight ZrO₂ and 0.7-3.5% by weightof fluoride at 1550 to 1650° C., the melting process including severalholding stages in the range of 400 to 1500° C., and cooling down thesaid mixture in the furnace in a controlled manner and at a rate of 60°C./h to 300° C./h, the cooling process lasting for 2 to 10 h andincluding two holding stages between 1000 and 1100° C. and between 800and 1000° C.
 11. The use of a glassy-crystalline material according toclaim 1 for manufacturing granulated materials; or ceramic bodies orceramic sheets having a dense or open-pore structure.